Abstract 769P
Background
Next generation sequencing (NGS) can identify tumor mutational burden (TMB) in urothelial carcinoma (UC) and reveal underlying driver mutations. TMB and APOBEC signatures are potential prognostic markers in UC and other tumors. Their value in predicting treatment outcomes to specific therapies in UC warrants further investigation.
Methods
We retrospectively reviewed UC cases assessed with UCSF500, an institutional NGS assay that uses hybrid capture enrichment of target DNA to interrogate 479 common cancer genes. Hypermutated tumors (HM) were defined as having TMB >10 mutations/Mb. Eligible HM tumors were also assessed for APOBEC signatures. Signatures were not assessed in non-HM (NHM) tumors due to low TMB. Log Rank test was used to determine differences in overall survival (OS) and progression free survival (PFS) among patient (pt) groups of interest.
Results
From 2015 to 2020, 75 pts with UC underwent UCSF500 testing. In this cohort, 46 pts were evaluable for TMB, of which 19 pts (41%) had HM tumors and the rest had NHM tumors (27 pts). Another 29 pts had unknown TMB status. Among 19 HM pts, all 16 pts who were evaluable for mutational signatures had APOBEC signatures; the remaining 3 pts were not evaluable. Pts grouped as Other (56 pts) included 27 NHM pts and the 29 pts with unknown TMB status. The table shows the comparison of clinical outcomes across relevant pt subsets from initial diagnosis and from treatment initiation with chemotherapy (chemo) or immunotherapy (IO). Table: 769P
| Comparison | N (pts) | Median Survival (months) | p-value |
| APOBEC vs Other | |||
| OS from Diagnosis | APOBEC (16) vs Other (56) | 125.3 vs 44.5 | 0.05 |
| From IO Start OS PFS | APOBEC (8) vs Other (25) | 12.4 vs 14.1 4.1 vs 3.3 | 0.27 0.25 |
| From Chemo Start OS PFS | APOBEC (5) vs Other (15) | 7.0 vs 13.1 4.3 vs 7.0 | 0.05 0.01 |
| HM vs NHM | |||
| OS from Diagnosis | HM (19) vs NHM (27) | 125.3 vs 35.7 | 0.06 |
| From IO Start OS PFS | HM (9) vs NHM (13) | 12.4 vs 14.1 4.1 vs 3.3 | 0.48 0.52 |
| From Chemo Start OS PFS | HM (6) vs NHM (8) | 7.0 vs 13.1 4.3 vs 9.1 | 0.04 <0.001 |
Conclusions
In this single-institution UC cohort, HM tumors were frequent and APOBEC signatures were commonly found in these tumors. APOBEC signatures and HM status (high TMB) were prognostic of improved OS from diagnosis but both also predicted inferior outcomes with chemotherapy treatment. These findings are hypothesis-generating and should be validated prospectively.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
N. Joseph: Shareholder/Stockholder/Stock options: Abiomed. E. Chan: Research grant/Funding (institution): Proscia. S. Porten: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Photocure; Advisory/Consultancy, Travel/Accommodation/Expenses: Bristol-Myers Squibb; Advisory/Consultancy: Kdx. J. Chou: Shareholder/Stockholder/Stock options: Array Biopharma; Shareholder/Stockholder/Stock options: Atara Biotherapeutics; Shareholder/Stockholder/Stock options: Celgene. T. Friedlander: Leadership role: Med BioGene; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: AstraZeneca; Honoraria (self), Travel/Accommodation/Expenses: MedImmune; Honoraria (self): EMD Serono; Honoraria (self), Research grant/Funding (institution): Seattle Genetics; Honoraria (self): Astellas; Advisory/Consultancy: Abbvie; Advisory/Consultancy: Dava Oncology; Advisory/Consultancy: Dendreon; Advisory/Consultancy: Foundation Medicine; Advisory/Consultancy, Research grant/Funding (self): Janssen; Advisory/Consultancy: Pfizer; Research grant/Funding (institution): Bristol-Myers Squibb; Research grant/Funding (institution): Incyte; Research grant/Funding (institution): Neon Therapeutics; Travel/Accommodation/Expenses: Genentech/Roche; Travel/Accommodation/Expenses: Jounce Therapeutics. L. Fong: Research grant/Funding (institution): Abbvie; Research grant/Funding (institution): Bavarian Nordic; Research grant/Funding (institution): BMS; Research grant/Funding (institution): Dendreon; Research grant/Funding (institution): Janssen; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Roche/GNE. E.J. Small: Advisory/Consultancy, Shareholder/Stockholder/Stock options: Fortis; Shareholder/Stockholder/Stock options: Harpoon Therapeutics; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Janssen; Advisory/Consultancy: Beigene; Advisory/Consultancy: Teon Therapeutics; Advisory/Consultancy: Tolero Pharmaceuticals; Research grant/Funding (institution): Merck. V.S. KOSHKIN: Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Dendreon; Advisory/Consultancy: Janssen. All other authors have declared no conflicts of interest.